Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have established cis-diamminedichloroplatinum(II) (cisplatin) resistant human small cell lung cancer cell lines, H69/CDDP0.2 and H69/CDDP, to investigate the mechanism of acquired resistance to cisplatin. H69/CDDP0.2 and H69/CDDP were 6- and 11-fold resistant to cisplatin compared with the H69 parental cell line. H69/CDDP was also resistant to cadmium chloride (2-fold), cis-diammine(glycolato)platinum (4-fold), 4-hydroperoxycyclophosphamide (3-fold) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosour ea (4-fold) if the drug concentrations that inhibit cell growth by 50% from growth inhibition assay were compared. There was no significant difference in the cisplatin accumulation among these cell lines. Although DNA interstrand cross-link formations, determined by filter elution assay in H69/CDDP0.2 and H69/CDDP, was decreased to 20 to 30% of that in H69 parental cells, the repair capacity of DNA interstrand cross-links was equivalent in all three cell lines. Intracellular glutathione content was equal in all cell lines. H69/CDDP had the highest glutathione S-transferase activity (H69, 11 nmol/min/mg protein, H69/CDDP0.2, 12 nmol/min/mg protein; H69/CDDP, 74 nmol/min/mg protein, respectively) and an overexpression of glutathione S-transferase pi mRNA. The drug concentrations that inhibit cell growth by 50% for cisplatin in all cell lines were decreased by treatment with ethacrynic acid, an inhibitor of glutathione S-transferase pi, but this did not alter the relative degree of resistance. Intracellular metallothionein content (H69, 14 pmol/mg protein, H69/CDDP0.2, 22 pmol/mg protein; H69/CDDP, 33 pmol/mg protein, respectively) and expression of metallothionein mRNA were correlated with the drug concentrations that inhibit cell growth by 50% of the three cell lines for cisplatin and cadmium chloride. The present study suggested the importance of metallothionein in the mechanisms of cisplatin resistance.
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PMID:Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. 164 16

Distribution of cadmium (Cd) in liver supernatant was examined by gel filtration chromatography after injecting Cd intravenously into female Wistar rats and also by adding Cd in vitro into the control supernatant. Supernatants were analyzed on an HPLC Asahipak GST-520 column and on-line ICP (inductively coupled argon plasma-atomic emission spectrometer) analysis of the eluate (HPLC-ICP). The relative intensity of the three main Cd-associated peaks changed with time after injection of Cd into rats. The three peaks were tentatively assigned as Cd-binding protein-I and -II (Cd-BP-I and -II) and metallothionein (MT) in the order of respective elution from the column. Relative affinities of Cd for the three peaks were determined by injecting different doses of Cd into rats as follows: MT greater than Cd-BP-II greater than Cd-BP-I. Cd-BP-II was assigned as the major Cd-BP other than MT in the liver supernatant and it contained zinc that can be replaced by Cd. Comparison between the in vivo and in vitro Cd distributions indicated that the former distribution is not reproducible under any in vitro conditions examined and the latter distribution is dependent mostly upon incubation temperature.
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PMID:Different distribution of cadmium in the liver supernatant between in vivo and in vitro. 181 Dec 82

Studies have suggested that the alpha class glutathione S-transferase (GST) may protect cells from the chemotherapeutic drugs chlorambucil and melphalan. In order to further define the function of human alpha class GST, a complementary DNA which encodes it was ligated into an expression vector under the direction of the human metallothionein-IIA promoter and stably transfected into human MCF-7 breast cancer cells in conjunction with the G418-selectable plasmid pSV2neo. Clonal cell lines were identified which expressed increased levels of GST enzyme activity (2.2- to 5.6-fold). The transfected cell lines also had increased peroxidase activity using cumene hydroperoxide as the substrate (1.9- to 3.8-fold) which is consistent with the intrinsic peroxidase activity of alpha class GSTs. Southern blot analysis indicated that genomic DNA from these cells contained a fragment indistinguishable from the transfected alpha class GST complementary DNA (850 base pairs); Northern blot analysis of total cellular RNA indicated that these cells contained appropriately sized alpha class GST RNA (980 nucleotides); and Western blot analysis indicated that, while MCF-7 cells contained no detectable alpha class GST protein, the transfected cells contained markedly elevated levels of alpha class GST but no detectable mu or pi class GST. These alpha class GST transfected cells had increased resistance to ethacrynic acid (2.1- to 3.0-fold). However, the transfected cells failed to show any increased resistance measured at the drug dosage which inhibited 50% of the colony formation to the chemotherapeutic drugs chlorambucil, melphalan, Adriamycin, or cisplatin under conditions of either continuous or 1-h drug exposure. Neither was there any change in sensitivity to the cytotoxins benzo(a)pyrene, benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide (anti), or 1-chloro-2,4-dinitrobenzene. These studies indicate that expression of this human alpha class GST by itself in MCF-7 human breast cancer cells does not confer resistance to the chemotherapeutic drugs tested under the conditions used in these studies.
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PMID:Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human alpha class glutathione S-transferase gene. 198 77

To elucidate the mechanism(s) of cisplatin resistance, we have characterized a human non-small cell lung cancer cell line (PC-9/CDDP) selected from the wild type (PC-9) for acquired resistance to cisplatin. PC-9/CDDP demonstrated 28-fold resistance to cisplatin, with cross resistance to other chemotherapeutic drugs including chlorambucil (X 6.3), melphalan (X 3.7) and 3-[(4-amino-2-methyl-5-pyrimidinyl)]methyl-1-(2-chloroethyl)-1-nitros our ea (ACNU) (x 3.9). There was no expression of mdr-1 mRNA in either wild-type or resistant cells. The mRNA and protein levels of glutathione S-transferase (GST) pi were similar in the two lines. A GST-mu isozyme was present in equal amounts and the activities of selenium-dependent and independent glutathione peroxidase and glutathione reductase were unchanged. The mRNA level of human metallothionein IIA and the total intracellular metallothionein levels were reduced in the resistant cells. Significantly increased intracellular glutathione (GSH) levels were found in the resistant cells (20.0 vs 63.5 nmol/mg protein) and manipulation of these levels with buthionine sulfoximine produced a partial sensitization to either cisplatin or chlorambucil. Increased GSH probably also played a role in determining cadmium chloride resistance of the PC-9/CDDP, even though this cell line had a reduced metallothionein level. Also contributing to the cisplatin resistance phenotype was a reduced intracellular level of platinum in the PC-9/CDDP. Thus, at least two distinct mechanisms have been selected in the resistant cells which confer the phenotype and allow degrees of cross resistance to other electrophilic drugs.
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PMID:Determinants of drug response in a cisplatin-resistant human lung cancer cell line. 211 1

We compared the regulation of gamma-glutamyl transferase (gamma GT) and glutathione-S-transferase-P (GST-P) expression in rat liver epithelial cells (228 cells) and a line derived from them (C5 cells) by stable transfection with a metallothionein-activated ras fusion gene (MTrasT24). Earlier studies demonstrated that steady state RNA levels of these genes are increased after transformation of liver cells by MTrasT24 (Proc. Natl. Acad. Sci., 85, 344-348, 1988). In the present study, we found that the rate of gamma GT transcription increased approximately 20 fold after transformation by MTrasT24 while the rate of GST-P transcription increased no more than two fold. However, the stability of GST-P RNA was increased about 3 fold in these cells. Comparisons of gamma GT RNA stability were not possible since nontransformed liver cells (228) contain little or no gamma GT RNA. Thus, the accumulation of gamma GT RNA in C5 cells is heavily dependent on increased rates of transcription while the more modest increases in GST-P RNA levels result in large part from increased RNA stability. In ras transformed cells both transcriptional and post-transcriptional events contribute to the increased steady state RNA levels of cellular genes.
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PMID:Two genes associated with liver cancer are regulated by different mechanisms in rasT24 transformed liver epithelial cells. 256

Increased expression of the glutathione S-transferase (GST; E.C.2.5.1.18) pi class isozyme is associated with both malignant transformation and drug resistance, as well as with decreased estrogen receptor content in breast cancer. In order to further characterize the role of this enzyme in drug resistance, we cloned the cDNA encoding the human isozyme GST pi and developed two eukaryotic expression vectors using this cDNA and either the human metallothionein IIa or cytomegalovirus immediate-early promoters. These GST pi expression vectors were cotransfected with pSV2neo into drug-sensitive MCF-7 human breast cancer cells, which have low amounts of GST activity and which do not express GST pi. The transfected cells were selected for G418 resistance and individual clones were screened for GST activity. Three clones that demonstrated increased GST activity were selected for further study. Immunoprecipitation studies demonstrated that the increase in GST activity in these clones was due to expression of GST pi. Although the total GST activity of the positive clones was increased as much as 15-fold over that in wild-type MCF-7 cells, there was no change in glutathione peroxidase activity, as measured using cumene hydroperoxide as a substrate. Immunoblot studies revealed that the increased GST enzyme produced in the transfected cells was identical in size to endogenous GST pi. Southern blot analysis demonstrated the incorporation of the GST pi expression vector into the genome of the positive clones and Northern blot analysis showed that the transfected genes made a hybrid GST pi RNA that was slightly larger than the endogenous GST pi RNA. Primer extension studies demonstrated that this increase in length corresponded to the added length of the 5' leader sequence of the expression vector. The effect of increased GST pi activity on the sensitivity of the transfected clones to several cytotoxic agents was assessed by colony-forming assay. The transfected clones were slightly more resistant (1.3-4.1-fold) to benzo(a)pyrene and its toxic metabolite benzo(a)pyrene-(anti)-7,8-dihydrodiol-9,10-epoxide, as well as to ethacrynic acid (3.1-to 4.4-fold). Although increased GST pi expression is found in MCF-7 cells selected for doxorubicin resistance, the transfected clones were not consistently more resistant to doxorubicin than control cells. In addition, the transfected cells were not resistant to either melphalan or (cis)-platinum, even though conjugation with glutathione is known to play a role in the detoxification of both of these drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Elevation of pi class glutathione S-transferase activity in human breast cancer cells by transfection of the GST pi gene and its effect on sensitivity to toxins. 274 27

Plaice were treated with an acute dose of a polyaromatic hydrocarbon (3-methylcholanthrene, 3-MC) or cadmium, or 3-MC and cadmium by i.p. injection. The effects on hepatic detoxication systems, cytochrome P-450 (ethoxyresorufin O-deethylase, EROD), UDP-glucuronyl transferase, glutathione S-transferase, glutathione peroxidase activities, total glutathione (GSH), metallothionein and Cd and Zn in the cytosol were studied over a 14 day period. 3-MC increased EROD (7-18-fold), glucuronyl transferase (40%) and GSH transferase (200%) activities, whereas GSH peroxidase activity decreased by 60%. Cd treatment inhibited EROD (90%), GSH transferase (90%) and GSH peroxidase (30%) activities and displaced Zn. Total GSH levels increased (200%) prior to onset of metallothionein synthesis (6 days). Cotreatment with 3-MC and Cd led to a marked increase in GSH levels (300%) but the onset of metallothionein synthesis was delayed by a week. Induction of enzyme activities was abolished, EROD activity was strongly inhibited and there was a transient 50-90% decrease in glucuronyl transferase, GSH transferase and GSH peroxidase activities on days 2 and 3 after treatment. The results indicate that a polyaromatic hydrocarbon could result in increased peroxidative damage, the heavy metal Cd can severely inhibit organic xeno- and endobiotic metabolism and that the effects of both agents may be synergistic.
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PMID:The time course of effects of cadmium and 3-methylcholanthrene on activities of enzymes of xenobiotic metabolism and metallothionein levels in the plaice, Pleuronectes platessa. 286 5

We studied the effects of a zinc-inducible metallothionein-ras fusion gene (MTrasT24) in cultured rat liver epithelial (RLE) cells on expression of two genes induced during liver carcinogenesis in vivo: gamma-glutamyltransferase [(5-glutamyl)-peptide:amino acid 5-glutamyltransferase, EC 2.3.2.2] and glutathione S-transferase-P (RX:glutathione R-transferase, EC 2.5.1.18). Expression of MTrasT24 increased steady-state RNA levels of gamma-glutamyltransferase and glutathione transferase-P 6- to 100-fold and 1.6- to 6-fold, respectively; in contrast, levels of alpha-tubulin RNA fell slightly or were unchanged. RNA gel blots verified that gamma-glutamyltransferase and glutathione transferase-P RNAs were of the appropriate size, and results from immunocytochemistry on transfected cells demonstrated that RLE cells carrying MTrasT24 synthesized immunoreactive, appropriately localized gamma-glutamyltransferase and glutathione transferase-P. Zinc induction studies indicated that gamma-glutamyltransferase and glutathione transferase-P RNA levels were directly dependent on MTrasT24 RNA levels. These data suggest that expression of gamma-glutamyltransferase and glutathione transferase-P expression are part of a reorientation of cellular gene expression during carcinogenesis and that activated ras expression, like chemical carcinogens, can bring about this change.
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PMID:MTrasT24, a metallothionein-ras fusion gene, modulates expression in cultured rat liver cells of two genes associated with in vivo liver cancer. 289 74

The present study was conducted to elucidate the protective action of simultaneous selenium administration against acute cadmium toxicity. The remarkable testicular damages caused by cadmium, that is, hemorrhagic inflammation, atrophy and necrosis, were lessened by simultaneous selenium administration. Cadmium concentration in blood, especially in plasma, increased significantly during the early period after cadmium administration with selenium. Cadmium and selenium in plasma were found in the same fractions of high molecular weight reported by previous workers as the high molecular weight complex containing cadmium and selenium. Cadmium in testis was also noted in the high molecular weight fraction during the early period. However, cadmium in the high molecular weight fraction of plasma and testis were unstable and decreased rapidly by lapse in time. Cadmium concentration in liver was lower than that in the group administered cadmium alone during the increasing phase of plasma cadmium. However, in contrast with the decreased cadmium level in plasma, cadmium in liver and testis increased gradually. Cadmium increased in liver and testis were also found in the metallothionein fraction. In the testis protected from acute cadmium toxicity, the inhibitory effect of glutathione S-transferase activity by cadmium was not detectable and the activity was maintained at the level of the control (saline administered group). Moreover, the increased cadmium in the metallothionein fraction was related to the decrease of cadmium in the high molecular weight fraction of the testis homogenate. In addition, a positive correlation was observed between metallothionein concentration and glutathione S-transferase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The protective effect of simultaneous selenium administration on acute cadmium toxicity and metallothionein]. 322

Several aspects of the effects of zinc on the metabolism of glutathione were examined in the Chinese hamster cell (line CHO) and in three derived sublines which differ in their resistance to the thiol reactive heavy metal cadmium. In the parental CHO cell, which does not induce the synthesis of metallothionein in response to zinc, glutathione levels remained approximately constant during the first 6 hr of zinc exposure. In the resistant cell lines, which induce the synthesis of metallothionein in response to zinc, the glutathione levels dropped transiently during zinc exposure. In all cell lines except the most cadmium resistant line, the glutathione levels after 12 hr were increased up to 3-fold relative to pretreatment levels. Similarly, the glutathione S-transferase activity measured by the conjugation of 1-chloro-2,4-dinitrobenzene to glutathione was increased after 9-12 hr of zinc treatment in all except the most highly cadmium resistant cell line. Glutathione reductase was not affected consistently by zinc treatment; however, the level of activity of this enzyme in the most highly cadmium resistant line was two to three times greater than that observed in the other cell lines. These effects are considered in relation to the zinc-induced protection of these cells from the toxic effect of the alkylating agent melphalan.
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PMID:Zinc effects on glutathione metabolism relationship to zinc-induced protection from alkylating agents. 663 70


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